Myasthenic Antibodies Cross-Link Acetylcholine Receptors to Accelerate Degradation

The decrease of acetylcholine receptors at neuromuscular junctions of myasthenic patients has been attributed to an antibody-mediated autoimmune process that accelerates receptor degradation. We studied the mechanism of this process in skeletal-muscle cultures, using intact antibodies and antibody fragments. Addition of myasthenic IgG or its divalent fragment, F(ab′)₂, to cultures accelerated the rate of acetylcholine-receptor degradation threefold. By contrast, the monovalent fragment, Fab, from myasthenic serum had no effect on degradation, although it bound to acetylcholine receptors. Addition of a second, “piggyback” antibody to cross-link the Fab:receptor complexes resulted in a threefold increase of the degradation rate. Similarly, when acetylcholine receptors with bound α-bungarotoxin were cross-linked by the addition of specific antibody against α-bungarotoxin, the degradation rate increased approximately threefold. The effect of myasthenic patients’ antibodies in accelerating degradation of acetylcholine receptors is attributed to their ability to cross-link the receptors. (N Engl J Med 298:1116–1122, 1978) MYASTHENIA gravis is a neuromuscular disorder characterized by weakness and fatigability of muscles. It is now well established that there is a decrease of acetylcholine receptors at neuromuscular junctions of myasthenic patients,^{1 2 3 4 5} sufficient to account for the typical clinical and electrophysiologic manifestations of the disorder.⁶ Abundant evidence indicates that the pathogenesis of myasthenia gravis involves an autoimmune attack directed against acetylcholine receptors (reviewed by Drachman⁷ and Lennon⁸). A humoral immune mechanism has been implicated in myasthenia by the finding of circulating antibodies against acetylcholine receptor^{9 10 11} capable of reproducing the basic features of the disease on passive transfer to mice.